PROJECT SUMMARY/ABSTRACT The Cancer Genetics and Epigenetics (CGE) Program was formed in 2012 and consists of 52 members (36 primary, 15 associate and 1 adjunct) from 10 departments. Dr. Sharon Dent, an international leader in defining the function and regulation of histone-modifying proteins, leads the program. Dr. Guillermina Lozano, a leading authority on the p53 tumor suppressor pathway, and Dr. David Johnson, an expert on the functions of the E2F family of proteins in transcription, DNA repair and cell growth control, serve as co-leaders. The major scientific goal of the program is to define the genetic, epigenetic and mechanistic changes that influence cancer to develop new and effective means to positively impact cancer diagnosis, treatment and cure. The program is organized around 3 major themes: 1) Oncogenes and Tumor Suppressors, 2) Epigenetic Regulators, and 3) Genome Maintenance. Each theme is addressed by a specific aim. Aim 1: To define molecular pathways important in human cancers using genetic and genomic approaches in model organisms, cellular systems and patient-derived tissues; Aim 2: To define functions of epigenetic regulators in normal and disease states and explore how these functions can be exploited for development of new therapeutics or diagnostics; Aim 3: To define the molecular machinery that responds to DNA damage and other stresses to maintain genome integrity and tissue homeostasis and to understand how dysfunction of these mechanisms contributes to cancer. CGE annual direct funding totals $10.2M with $2.5M from the NCI, $7.7M from other peer-reviewed sources, such as CPRIT, the Leukemia & Lymphoma Society, the American Cancer Society, and breast and prostate cancer research funding from the U.S. Department of Defense. Total program peer-reviewed funding reflects an increase of 7% since the last competitive renewal. The program has also produced 779 published papers, with 132 (17%) reflecting intra- programmatic collaborations (an increase of 5%), 270 (35%) reflecting inter-programmatic collaborations (an increase of 6%), and 571 (73%) reflecting inter-institutional collaborations. Sixty-five percent of articles appeared in journals with IF >5, and 27% of articles were published in journals with IF >10, including N Engl J Med, Nature, Science, Lancet Oncol, Cell, Cancer Cell, Cancer Discov, J Clin Oncol, and JAMA Oncol. Program members have collectively used all CCSG shared resources. Research accomplishments during the last grant period include definition of the origin and evolution of breast tumor cell heterogeneity, development of the first small- molecule inhibitor of the TRIM24 bromodomain, identification of the YEATS domain as a new epigenetic ?reader? of acetylated lysine implicated in leukemia and non-small cell lung cancer, and the discovery that the BRCA1- interacting protein ABRAXAS and the related protein ABRO1, maintain genome integrity. These and other discoveries reflect the impact of our contributions to defining the mutations, epigenetic alterations, and cellular mechanisms that underlie oncogenesis.